The proposed Project includes a complex interplay of both microbicide product development with single agent and combination microbicide products uniquely delivered to both the vaginal and rectal compartments, as well as microbicide science advancement in which the active microbicides will be utilized as tools to better understand microbicide dosing, pharmacokinetics and pharmacodynamics in explants, nonhuman primates and humans, and acceptability/user perception. The product development components consist of the dual acting entry and nonnucleoside reverse transcriptase inhibitor IQP-0528 (a pyrimidinedione with subnanomolar activity against clinical strains of HIV-1) used alone and in combination with tenofovir in dual compartment (DuoGels) gels and smart suppository/pessary (Smart Suppository) delivery vehicles that will enable dosing in both vaginal and rectal compartments. We believe the potential advancements in product development (new microbicide agents, combination products, long lasting delivery technology, dual compartment delivery technology) and microbicide science (dosing estimation, pharmacokinetics, pharmacodynamics, in vitro, ex vivo, and in vivo modeling, effects of seminal and vaginal fluids, acceptability testing methods) make this proposal both inherently novel and important to the field of microbicide science in regard to the development of the next generation of microbicide products. In whole, the Project also provides for the development of novel PK/PD assays, novel single and combination products, novel delivery strategies, and novel microbicide development advancements to better understand and prioritize the development and use of microbicide products. The Administrative Core will play a critical and essential role in ensuring the smooth integration of the various Projects and Cores included in this cooperative agreement research program. The successful performance of this Project requires a high degree of communication and interaction between the various Projects, the Cores, and the Corporate Partner. The Administrative Core will be responsible for managing and enhancing this constructive and synergistic interplay between the participating scientific groups.